Proteins lysine acetyltransferases (HATs or PATs) acetylate histones and other proteins

Proteins lysine acetyltransferases (HATs or PATs) acetylate histones and other proteins and are principally modeled as transcriptional coactivators. Analysis of CBP and p300 mutant mouse fibroblasts reveals CBP/p300 are together chiefly responsible for the global acetylation of histone H3 residues K18 and K27 and contribute to other locus-specific histone acetylation events. CBP/p300 can also be important for transcription but the recruitment of CBP/p300 and their associated histone acetylation marks do not absolutely correlate with a requirement for gene activation. Rather it appears that target gene context (e.g. DNA sequence) influences the extent to which CBP LBH589 and p300 are necessary for transcription. analysis p44erk1 of histone mutations in mammals The function of histone PTMs in mammals remains uncertain because the multiple genes encoding each canonical histone renders mutational analysis unfeasible in most instances. Exceptions to this limitation occur when analyzing histone variants that have few gene copies or when assessing putative gain-of function histone mutations such as those identified in pediatric glioblastoma and glioma (e.g. H3.3 K27M) [4 5 For instance knockout of the H2A variant H2A.Z reveals that it is required for early mouse development [6] whereas loss of another variant macroH2A1 has subtle effects on mouse physiology and gene expression [7 8 The difficulty of testing histone point mutations in mammals has therefore contributed to the uncertainty of whether canonical histone PTMs are correlative with gene expression or causal. Yeast histone mutants suggest subtle or specific roles for many histone PTMs In baker’s yeast however histone mutations can be easily made and numerous studies show that histone PTMs might not be as essential as their correlative behavior with transcription would suggest [9-14]. For instance a systematic analysis of 486 different histone H3 and H4 mutations in yeast (where every residue was mutated at least one way) showed that only 11 of 79 N-terminal tail deletions resulted in lethality a phenotype that also depends to some extent on strain background [9]. (In the filamentous fungus and in mice) the MYST LBH589 family (and andand mice all die during embryogenesis with the compound heterozygous phenotype indicating that the combined amount of the two proteins is limiting [34 35 Interestingly mice exhibit characteristics of RTS including growth retardation LBH589 and craniofacial anomalies [36 37 implying LBH589 that some of the developmental functions of CBP are conserved between mice and man [36-40]. In contrast mice are slightly smaller and less thrifty than wild-type littermate controls but are otherwise grossly normal [35]. The early embryonic lethality observed in CBP and p300 knockout mice complicated efforts to understand the role of CBP and p300 in adult cell lineages. Subsequently the creation of conditional Cre/LoxP knockout alleles (and blocks the lifespan extension induced LBH589 by dietary restriction and hypothalamic expression of CBP is reportedly reduced in aging mice [53]. Such studies suggest that CBP HAT activity is a determinant of healthy LBH589 aging. In keeping with this notion mice are also lean and insulin-sensitized [54] and growing evidence places CBP/p300 in signalling pathways capable of promoting energy homeostasis [55 56 For example p300 acetylates the energy-state-sensor AMP kinase to inhibit its activity and promote lipid storage; AMPK acetylation is counter-regulated by the deacetylase HDAC1 which promotes lipid breakdown [57]. Accordingly CBP and p300 are receiving growing attention as potential therapeutic targets for the treatment of metabolic diseases and other age-related pathologies. CBP and p300 are important for whole animal energy homeostasis During fasting glucagon is secreted from the pancreas and promotes hepatic glucose production (HGP) by increasing liver intracellular cAMP and gluconeogenic gene expression [58]. Hepatic gluconeogenic gene transcription is stimulated via recruitment of HAT (CBP/p300) and non-HAT (CRTC CREB Regulated Transcription Coactivator) coactivators to CREB that is bound to target gene promoters [59 60 However fasting blood glucose levels and hepatic gluconeogenic.